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Soluble Epoxide Hydrolase as a Stroke Target

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Part of the book series: Springer Series in Translational Stroke Research ((SSTSR))

Abstract

Soluble epoxide hydrolase (sEH) is a promising therapeutic target for stroke. Both pharmacological inhibition and genetic knockout of sEH have shown protection in experimental models of cerebral ischemia. Additionally, human single-nucleotide polymorphisms in the gene that encodes for sEH, designated ephx2, have been correlated with stroke incidence and outcome. This chapter starts out by introducing sEH in the context of the five other mammalian epoxide hydrolases before delving specifically into sEH biology. Up-to-date research into sEH’s protein structure, role in metabolizing epoxyeicosatrienoic acids, regional localization in brain, as well as subcellular localization are discussed in relation to brain function and disease. The chapter concludes by evaluating the prospect of using sEH inhibitors in clinical trials for the treatment of stroke based on the Stroke Therapy Academic and Industry Roundtable criteria.

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References

  1. Holmquist M. Alpha/beta-hydrolase fold enzymes: structures, functions and mechanisms. Curr Protein Pept Sci. 2000;1:209–35.

    Article  PubMed  CAS  Google Scholar 

  2. Fleming I. Epoxyeicosatrienoic acids, cell signaling and angiogenesis. Prostaglandins Other Lipid Mediat. 2007;82:60–7.

    Article  PubMed  CAS  Google Scholar 

  3. Newman JW, Morisseau C, Hammock BD. Epoxide hydrolases: their roles and interactions with lipid metabolism. Prog Lipid Res. 2005;44:1–51.

    Article  PubMed  CAS  Google Scholar 

  4. Oesch F. Purification and specificity of a human microsomal epoxide hydratase. Biochem J. 1974;139:77–88.

    PubMed  CAS  Google Scholar 

  5. Friedberg T, Löllmann B, Becker R, Holler R, Oesch F. The microsomal epoxide hydrolase has a single membrane signal anchor sequence which is dispensable for the catalytic activity of this protein. Biochem J. 1994;303(Pt 3):967–72.

    PubMed  CAS  Google Scholar 

  6. Lu AY, Miwa GT. Molecular properties and biological functions of microsomal epoxide hydrase. Annu Rev Pharmacol Toxicol. 1980;20:513–31.

    Article  PubMed  CAS  Google Scholar 

  7. de Medina P, Paillasse MR, Segala G, Poirot M, Silvente-Poirot S. Identification and pharmacological characterization of cholesterol-5,6-epoxide hydrolase as a target for tamoxifen and AEBS ligands. Proc Natl Acad Sci U S A. 2010;107:13520–5.

    Article  PubMed  Google Scholar 

  8. Cronin A, Decker M, Arand M. Mammalian soluble epoxide hydrolase is identical to liver hepoxilin hydrolase. J Lipid Res. 2011;52(4):712–9.

    Article  PubMed  CAS  Google Scholar 

  9. Orning L, Gierse JK, Fitzpatrick FA. The bifunctional enzyme leukotriene-A4 hydrolase is an arginine aminopeptidase of high efficiency and specificity. J Biol Chem. 1994;269:11269–73.

    PubMed  CAS  Google Scholar 

  10. Rudberg PC, Tholander F, Andberg M, Thunnissen MMGM, Haeggström JZ. Leukotriene A4 hydrolase: identification of a common carboxylate recognition site for the epoxide hydrolase and aminopeptidase substrates. J Biol Chem. 2004;279:27376–82.

    Article  PubMed  CAS  Google Scholar 

  11. Knehr M, Thomas H, Arand M, Gebel T, Zeller HD, Oesch F. Isolation and characterization of a cDNA encoding rat liver cytosolic epoxide hydrolase and its functional expression in Escherichia coli. J Biol Chem. 1993;268:17623–7.

    PubMed  CAS  Google Scholar 

  12. Newman JW, Morisseau C, Harris TR, Hammock BD. The soluble epoxide hydrolase encoded by EPXH2 is a bifunctional enzyme with novel lipid phosphate phosphatase activity. Proc Natl Acad Sci U S A. 2003;100:1558–63.

    Article  PubMed  CAS  Google Scholar 

  13. Beetham JK, Grant D, Arand M, Garbarino J, Kiyosue T, Pinot F, et al. Gene evolution of epoxide hydrolases and recommended nomenclature. DNA Cell Biol. 1995;14:61–71.

    Article  PubMed  CAS  Google Scholar 

  14. Harris TR, Aronov PA, Hammock BD. Soluble epoxide hydrolase homologs in Strongylocentrotus purpuratus suggest a gene duplication event and subsequent divergence. DNA Cell Biol. 2008;27:467–77.

    Article  PubMed  CAS  Google Scholar 

  15. Harris TR, Morisseau C, Walzem RL, Ma SJ, Hammock BD. The cloning and characterization of a soluble epoxide hydrolase in chicken. Poult Sci. 2006;85:278–87.

    PubMed  CAS  Google Scholar 

  16. Argiriadi MA, Morisseau C, Hammock BD, Christianson DW. Detoxification of environmental mutagens and carcinogens: structure, mechanism, and evolution of liver epoxide hydrolase. Proc Natl Acad Sci U S A. 1999;96:10637–42.

    Article  PubMed  CAS  Google Scholar 

  17. Gomez GA, Morisseau C, Hammock BD, Christianson DW. Structure of human epoxide hydrolase reveals mechanistic inferences on bifunctional catalysis in epoxide and phosphate ester hydrolysis. Biochemistry. 2004;43:4716–23.

    Article  PubMed  CAS  Google Scholar 

  18. Tran KL, Aronov PA, Tanaka H, Newman JW, Hammock BD, Morisseau C. Lipid sulfates and sulfonates are allosteric competitive inhibitors of the N-terminal phosphatase activity of the mammalian soluble epoxide hydrolase. Biochemistry. 2005;44:12179–87.

    Article  PubMed  CAS  Google Scholar 

  19. Przybyla-Zawislak BD, Srivastava PK, Vazquez-Matias J, Mohrenweiser HW, Maxwell JE, Hammock BD, et al. Polymorphisms in human soluble epoxide hydrolase. Mol Pharmacol. 2003;64:482–90.

    Article  PubMed  CAS  Google Scholar 

  20. Enayetallah AE, Grant DF. Effects of human soluble epoxide hydrolase polymorphisms on isoprenoid phosphate hydrolysis. Biochem Biophys Res Commun. 2006;341:254–60.

    Article  PubMed  CAS  Google Scholar 

  21. Cronin A, Mowbray S, Dürk H, Homburg S, Fleming I, Fisslthaler B, et al. The N-terminal domain of mammalian soluble epoxide hydrolase is a phosphatase. Proc Natl Acad Sci U S A. 2003;100:1552–7.

    Article  PubMed  CAS  Google Scholar 

  22. Cronin A, Homburg S, Dürk H, Richter I, Adamska M, Frère F, et al. Insights into the catalytic mechanism of human sEH phosphatase by site-directed mutagenesis and LC-MS/MS analysis. J Mol Biol. 2008;383:627–40.

    Article  PubMed  CAS  Google Scholar 

  23. EnayetAllah AE, Luria A, Luo B, Tsai H, Sura P, Hammock BD, et al. Opposite regulation of cholesterol levels by the phosphatase and hydrolase domains of soluble epoxide hydrolase. J Biol Chem. 2008;283:36592–8.

    Article  PubMed  CAS  Google Scholar 

  24. Arand M, Cronin A, Oesch F, Mowbray SL, Jones TA. The telltale structures of epoxide hydrolases. Drug Metab Rev. 2003;35:365–83.

    Article  PubMed  CAS  Google Scholar 

  25. Enayetallah AE, French RA, Barber M, Grant DF. Cell-specific subcellular localization of soluble epoxide hydrolase in human tissues. J Histochem Cytochem. 2006;54:329–35.

    Article  PubMed  CAS  Google Scholar 

  26. Luo B, Norris C, Bolstad ESD, Knecht DA, Grant DF. Protein quaternary structure and expression levels contribute to peroxisomal-targeting-sequence-1-mediated peroxisomal import of human soluble epoxide hydrolase. J Mol Biol. 2008;380:31–41.

    Article  PubMed  CAS  Google Scholar 

  27. Lundgren B, DePierre JW. Proliferation of peroxisomes and induction of cytosolic and microsomal epoxide hydrolases in different strains of mice and rats after dietary treatment with clofibrate. Xenobiotica. 1989;19:867–81.

    Article  PubMed  CAS  Google Scholar 

  28. Enayetallah AE, French RA, Thibodeau MS, Grant DF. Distribution of soluble epoxide hydrolase and of cytochrome P450 2C8, 2C9, and 2J2 in human tissues. J Histochem Cytochem. 2004;52:447–54.

    Article  PubMed  CAS  Google Scholar 

  29. Sura P, Sura R, Enayetallah AE, Grant DF. Distribution and expression of soluble epoxide hydrolase in human brain. J Histochem Cytochem. 2008;56:551–9.

    Article  PubMed  CAS  Google Scholar 

  30. Shin J, Engidawork E, Delabar J, Lubec G. Identification and characterisation of soluble epoxide hydrolase in mouse brain by a robust protein biochemical method. Amino Acids. 2005;28:63–9.

    Article  PubMed  CAS  Google Scholar 

  31. Zhang W, Otsuka T, Sugo N, Ardeshiri A, Alhadid YK, Iliff JJ, et al. Soluble epoxide hydrolase gene deletion is protective against experimental cerebral ischemia. Stroke. 2008;39:2073–8.

    Article  PubMed  CAS  Google Scholar 

  32. Zhang W, Iliff JJ, Campbell CJ, Wang RK, Hurn PD, Alkayed NJ. Role of soluble epoxide hydrolase in the sex-specific vascular response to cerebral ischemia. J Cereb Blood Flow Metab. 2009;29:1475–81.

    Article  PubMed  CAS  Google Scholar 

  33. Koerner IP, Zhang W, Cheng J, Parker S, Hurn PD, Alkayed NJ. Soluble epoxide hydrolase: regulation by estrogen and role in the inflammatory response to cerebral ischemia. Front Biosci. 2008;13:2833–41.

    Article  PubMed  CAS  Google Scholar 

  34. Sinal CJ, Miyata M, Tohkin M, Nagata K, Bend JR, Gonzalez FJ. Targeted disruption of soluble epoxide hydrolase reveals a role in blood pressure regulation. J Biol Chem. 2000;275:40504–10.

    Article  PubMed  CAS  Google Scholar 

  35. Koerner IP, Jacks R, DeBarber AE, Koop D, Mao P, Grant DF, et al. Polymorphisms in the human soluble epoxide hydrolase gene EPHX2 linked to neuronal survival after ischemic injury. J Neurosci. 2007;27:4642–9.

    Article  PubMed  CAS  Google Scholar 

  36. Bianco RA, Agassandian K, Cassell MD, Spector AA, Sigmund CD. Characterization of transgenic mice with neuron-specific expression of soluble epoxide hydrolase. Brain Res. 2009;1291:60–72.

    Article  PubMed  CAS  Google Scholar 

  37. Iliff JJ, Close LN, Selden NR, Alkayed NJ. A novel role for P450 eicosanoids in the neurogenic control of cerebral blood flow in the rat. Exp Physiol. 2007;92:653–8.

    PubMed  CAS  Google Scholar 

  38. Zhang W, Koerner IP, Noppens R, Grafe M, Tsai H, Morisseau C, et al. Soluble epoxide hydrolase: a novel therapeutic target in stroke. J Cereb Blood Flow Metab. 2007;27:1931–40.

    Article  PubMed  CAS  Google Scholar 

  39. Marowsky A, Burgener J, Falck JR, Fritschy J, Arand M. Distribution of soluble and microsomal epoxide hydrolase in the mouse brain and its contribution to cerebral epoxyeicosatrienoic acid metabolism. Neuroscience. 2009;163:646–61.

    Article  PubMed  CAS  Google Scholar 

  40. Rawal S, Morisseau C, Hammock BD, Shivachar AC. Differential subcellular distribution and colocalization of the microsomal and soluble epoxide hydrolases in cultured neonatal rat brain cortical astrocytes. J Neurosci Res. 2009;87:218–27.

    Article  PubMed  CAS  Google Scholar 

  41. Imig JD, Hammock BD. Soluble epoxide hydrolase as a therapeutic target for cardiovascular diseases. Nat Rev Drug Discov. 2009;8:794–805.

    Article  PubMed  CAS  Google Scholar 

  42. Capdevila JH, Falck JR, Harris RC. Cytochrome P450 and arachidonic acid bioactivation. Molecular and functional properties of the arachidonate monooxygenase. J Lipid Res. 2000;41:163–81.

    PubMed  CAS  Google Scholar 

  43. Spector AA, Norris AW. Action of epoxyeicosatrienoic acids on cellular function. Am J Physiol Cell Physiol. 2007;292:C996–1012.

    Article  PubMed  CAS  Google Scholar 

  44. Daikh BE, Lasker JM, Raucy JL, Koop DR. Regio- and stereoselective epoxidation of arachidonic acid by human cytochromes P450 2C8 and 2C9. J Pharmacol Exp Ther. 1994;271:1427–33.

    PubMed  CAS  Google Scholar 

  45. Gross GJ, Hsu A, Falck JR, Nithipatikom K. Mechanisms by which epoxyeicosatrienoic acids (EETs) elicit cardioprotection in rat hearts. J Mol Cell Cardiol. 2007;42:687–91.

    Article  PubMed  CAS  Google Scholar 

  46. Campbell WB, Fleming I. Epoxyeicosatrienoic acids and endothelium-dependent responses. Pflugers Arch. 2010;459:881–95.

    Article  PubMed  CAS  Google Scholar 

  47. Cipolla MJ, Smith J, Kohlmeyer MM, Godfrey JA. SKCa and IKCa channels, myogenic tone, and vasodilator responses in middle cerebral arteries and parenchymal arterioles: effect of ischemia and reperfusion. Stroke. 2009;40:1451–7.

    Article  PubMed  Google Scholar 

  48. Simpkins AN, Rudic RD, Schreihofer DA, Roy S, Manhiani M, Tsai H, et al. Soluble epoxide inhibition is protective against cerebral ischemia via vascular and neural protection. Am J Pathol. 2009;174:2086–95.

    Article  PubMed  CAS  Google Scholar 

  49. Iliff JJ, Alkayed NJ. Soluble epoxide hydrolase inhibition: targeting multiple mechanisms of ischemic brain injury with a single agent. Future Neurol. 2009;4:179–99.

    Article  PubMed  CAS  Google Scholar 

  50. Larsen BT, Miura H, Hatoum OA, Campbell WB, Hammock BD, Zeldin DC, et al. Epoxyeicosatrienoic and dihydroxyeicosatrienoic acids dilate human coronary arterioles via BK(Ca) channels: implications for soluble epoxide hydrolase inhibition. Am J Physiol Heart Circ Physiol. 2006;290:H491–9.

    Article  PubMed  CAS  Google Scholar 

  51. Watanabe H, Vriens J, Prenen J, Droogmans G, Voets T, Nilius B. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature. 2003;424:434–8.

    Article  PubMed  CAS  Google Scholar 

  52. Behm DJ, Ogbonna A, Wu C, Burns-Kurtis CL, Douglas SA. Epoxyeicosatrienoic acids function as selective, endogenous antagonists of native thromboxane receptors: identification of a novel mechanism of vasodilation. J Pharmacol Exp Ther. 2009;328:231–9.

    Article  PubMed  CAS  Google Scholar 

  53. Yang C, Kwan Y, Au AL, Poon CC, Zhang Q, Chan S, et al. 14,15-Epoxyeicosatrienoic acid induces vasorelaxation through the prostaglandin EP(2) receptors in rat mesenteric artery. Prostaglandins Other Lipid Mediat. 2010;93:44–51.

    Article  PubMed  CAS  Google Scholar 

  54. Cowart LA, Wei S, Hsu M, Johnson EF, Krishna MU, Falck JR, et al. The CYP4A isoforms hydroxylate epoxyeicosatrienoic acids to form high affinity peroxisome proliferator-activated receptor ligands. J Biol Chem. 2002;277:35105–12.

    Article  PubMed  CAS  Google Scholar 

  55. Fang X, Hu S, Xu B, Snyder GD, Harmon S, Yao J, et al. 14,15-Dihydroxyeicosatrienoic acid activates peroxisome proliferator-activated receptor-alpha. Am J Physiol Heart Circ Physiol. 2006;290:H55–63.

    Article  PubMed  CAS  Google Scholar 

  56. Liu Y, Zhang Y, Schmelzer K, Lee T, Fang X, Zhu Y, et al. The antiinflammatory effect of laminar flow: the role of PPARgamma, epoxyeicosatrienoic acids, and soluble epoxide hydrolase. Proc Natl Acad Sci U S A. 2005;102:16747–52.

    Article  PubMed  CAS  Google Scholar 

  57. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature. 1998;391:79–82.

    Article  PubMed  CAS  Google Scholar 

  58. Wray J, Bishop-Bailey D. Epoxygenases and peroxisome proliferator-activated receptors in mammalian vascular biology. Exp Physiol. 2008;93:148–54.

    Article  PubMed  CAS  Google Scholar 

  59. Yu Z, Xu F, Huse LM, Morisseau C, Draper AJ, Newman JW, et al. Soluble epoxide hydrolase regulates hydrolysis of vasoactive epoxyeicosatrienoic acids. Circ Res. 2000;87:992–8.

    Article  PubMed  CAS  Google Scholar 

  60. Seubert JM, Sinal CJ, Graves J, DeGraff LM, Bradbury JA, Lee CR, et al. Role of soluble epoxide hydrolase in postischemic recovery of heart contractile function. Circ Res. 2006;99:442–50.

    Article  PubMed  CAS  Google Scholar 

  61. Sandberg M, Meijer J. Structural characterization of the human soluble epoxide hydrolase gene (EPHX2). Biochem Biophys Res Commun. 1996;221:333–9.

    Article  PubMed  CAS  Google Scholar 

  62. Gschwendtner A, Ripke S, Freilinger T, Lichtner P, Müller-Myhsok B, Wichmann H, et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with an increased risk of ischemic stroke in white Europeans. Stroke. 2008;39:1593–6.

    Article  PubMed  CAS  Google Scholar 

  63. Srivastava PK, Sharma VK, Kalonia DS, Grant DF. Polymorphisms in human soluble epoxide hydrolase: effects on enzyme activity, enzyme stability, and quaternary structure. Arch Biochem Biophys. 2004;427:164–9.

    Article  PubMed  CAS  Google Scholar 

  64. Sato K, Emi M, Ezura Y, Fujita Y, Takada D, Ishigami T, et al. Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred. J Hum Genet. 2004;49:29–34.

    Article  PubMed  CAS  Google Scholar 

  65. Wei Q, Doris PA, Pollizotto MV, Boerwinkle E, Jacobs DRJ, Siscovick DS, et al. Sequence variation in the soluble epoxide hydrolase gene and subclinical coronary atherosclerosis: interaction with cigarette smoking. Atherosclerosis. 2007;190:26–34.

    Article  PubMed  CAS  Google Scholar 

  66. Lee CR, North KE, Bray MS, Fornage M, Seubert JM, Newman JW, et al. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum Mol Genet. 2006;15:1640–9.

    Article  PubMed  CAS  Google Scholar 

  67. Burdon KP, Lehtinen AB, Langefeld CD, Carr JJ, Rich SS, Freedman BI, et al. Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study. Diab Vasc Dis Res. 2008;5:128–34.

    Article  PubMed  Google Scholar 

  68. Lee CR, Pretorius M, Schuck RN, Burch LH, Bartlett J, Williams SM, et al. Genetic variation in soluble epoxide hydrolase (EPHX2) is associated with forearm vasodilator responses in humans. Hypertension. 2011;57:116–22.

    Article  PubMed  CAS  Google Scholar 

  69. Fornage M, Lee CR, Doris PA, Bray MS, Heiss G, Zeldin DC, et al. The soluble epoxide hydrolase gene harbors sequence variation associated with susceptibility to and protection from incident ischemic stroke. Hum Mol Genet. 2005;14:2829–37.

    Article  PubMed  CAS  Google Scholar 

  70. Fava C, Montagnana M, Danese E, Almgren P, Hedblad B, Engström G, et al. Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes. Pharmacogenet Genomics. 2010;20:94–103.

    Article  PubMed  CAS  Google Scholar 

  71. Zhang L, Ding H, Yan J, Hui R, Wang W, Kissling GE, et al. Genetic variation in cytochrome P450 2J2 and soluble epoxide hydrolase and risk of ischemic stroke in a Chinese population. Pharmacogenet Genomics. 2008;18:45–51.

    Article  PubMed  Google Scholar 

  72. Lee J, Dahl M, Grande P, Tybjaerg-Hansen A, Nordestgaard BG. Genetically reduced soluble epoxide hydrolase activity and risk of stroke and other cardiovascular disease. Stroke. 2010;41:27–33.

    Article  PubMed  CAS  Google Scholar 

  73. Fornage M, Hinojos CA, Nurowska BW, Boerwinkle E, Hammock BD, Morisseau CHP, et al. Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats. Hypertension. 2002;40:485–90.

    Article  PubMed  CAS  Google Scholar 

  74. Monti J, Fischer J, Paskas S, Heinig M, Schulz H, Gösele C, et al. Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease. Nat Genet. 2008;40:529–37.

    Article  PubMed  CAS  Google Scholar 

  75. Corenblum MJ, Wise VE, Georgi K, Hammock BD, Doris PA, Fornage M. Altered soluble epoxide hydrolase gene expression and function and vascular disease risk in the stroke-prone spontaneously hypertensive rat. Hypertension. 2008;51:567–73.

    Article  PubMed  CAS  Google Scholar 

  76. Hutchens MP, Nakano T, Dunlap J, Traystman RJ, Hurn PD, Alkayed NJ. Soluble epoxide hydrolase gene deletion reduces survival after cardiac arrest and cardiopulmonary resuscitation. Resuscitation. 2008;76:89–94.

    Article  PubMed  CAS  Google Scholar 

  77. Manhiani M, Quigley JE, Knight SF, Tasoobshirazi S, Moore T, Brands MW, et al. Soluble epoxide hydrolase gene deletion attenuates renal injury and inflammation with DOCA-salt hypertension. Am J Physiol Renal Physiol. 2009;297:F740–8.

    Article  PubMed  CAS  Google Scholar 

  78. Zhang L, Vincelette J, Cheng Y, Mehra U, Chen D, Anandan S, et al. Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation, and dyslipidemia. Arterioscler Thromb Vasc Biol. 2009;29:1265–70.

    Article  PubMed  CAS  Google Scholar 

  79. Simpkins AN, Rudic RD, Roy S, Tsai HJ, Hammock BD, Imig JD. Soluble epoxide hydrolase inhibition modulates vascular remodeling. Am J Physiol Heart Circ Physiol. 2010;298:H795–806.

    Article  PubMed  CAS  Google Scholar 

  80. Revermann M, Schloss M, Barbosa-Sicard E, Mieth A, Liebner S, Morisseau C, et al. Soluble epoxide hydrolase deficiency attenuates neointima formation in the femoral cuff model of hyperlipidemic mice. Arterioscler Thromb Vasc Biol. 2010;30:909–14.

    Article  PubMed  CAS  Google Scholar 

  81. Luo P, Chang H, Zhou Y, Zhang S, Hwang SH, Morisseau C, et al. Inhibition or deletion of soluble epoxide hydrolase prevents hyperglycemia, promotes insulin secretion, and reduces islet apoptosis. J Pharmacol Exp Ther. 2010;334:430–8.

    Article  PubMed  CAS  Google Scholar 

  82. Luria A, Weldon SM, Kabcenell AK, Ingraham RH, Matera D, Jiang H, et al. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene-disrupted mice. J Biol Chem. 2007;282:2891–8.

    Article  PubMed  CAS  Google Scholar 

  83. Shen HC. Soluble epoxide hydrolase inhibitors: a patent review. Expert Opin Ther Pat. 2010;20:941–56.

    Article  PubMed  CAS  Google Scholar 

  84. Revermann M. Pharmacological inhibition of the soluble epoxide hydrolase-from mouse to man. Curr Opin Pharmacol. 2010;10:173–8.

    Article  PubMed  CAS  Google Scholar 

  85. Fang X, Hu S, Watanabe T, Weintraub NL, Snyder GD, Yao J, et al. Activation of peroxisome proliferator-activated receptor alpha by substituted urea-derived soluble epoxide hydrolase inhibitors. J Pharmacol Exp Ther. 2005;314:260–70.

    Article  PubMed  CAS  Google Scholar 

  86. Dorrance AM, Rupp N, Pollock DM, Newman JW, Hammock BD, Imig JD. An epoxide hydrolase inhibitor, 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA), reduces ischemic cerebral infarct size in stroke-prone spontaneously hypertensive rats. J Cardiovasc Pharmacol. 2005;46:842–8.

    Article  PubMed  CAS  Google Scholar 

  87. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, Savitz SI, et al. Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke. 2009;40:2244–50.

    Article  PubMed  Google Scholar 

  88. O’Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1,026 experimental treatments in acute stroke. Ann Neurol. 2006;59:467–77.

    Article  PubMed  Google Scholar 

  89. Anandan S, Webb HK, Chen D, Wang YJ, Aavula BR, Cases S, et al. 1-(1-acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea (AR9281) as a potent, selective, and orally available soluble epoxide hydrolase inhibitor with efficacy in rodent models of hypertension and dysglycemia. Bioorg Med Chem Lett. 2011;21:983–8.

    Article  PubMed  CAS  Google Scholar 

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Nelson, J.W., Alkayed, N.J. (2012). Soluble Epoxide Hydrolase as a Stroke Target. In: Lapchak, P., Zhang, J. (eds) Translational Stroke Research. Springer Series in Translational Stroke Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9530-8_13

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